Antimicrobial agents can be characterized based upon the pharmacokinetic-pharmacodynamic (PK-PD) measure most predictive of efficacy.i For antimicrobial agents, the three most common PK-PD measures are the percentage of time during the dosing interval that drug concentration remains above the MIC (% T>MIC), the ratio of the area under the concentration-time at 24 hours to the MIC (AUC0-24:MIC ratio) and the ratio of the maximal drug concentration to the MIC (Cmax:MIC). Preliminary identification of the PK-PD measure most closely associated with efficacy of an agent can be made by examining the agent's pattern of bactericidal activity in a dynamic infection model or by its pattern of bactericidal activity in a static in vitro test system in combination with knowledge of the presence and duration of post-antibiotic effects.
Some agents, such as tobramycin and ciprofloxacin, display a concentration-dependent pattern of bactericidal activity over a broad range of drug concentrations.ii That is, as drug concentration increases, so too does the rate and extent of bactericidal activity. On the other hand, other agents such as the β-lactam class agents display a time-dependent pattern of bactericidal activity.ii For these agents, concentration-dependent bacterial killing occurs over a narrow range of drug concentrations.
It is likely that prolonged exposure to antimicrobial agents exerts increased pressure for selection of microbial subpopulations that are resistant to the therapy administered.iii According to the mutant selection window hypothesis, there is an antibiotic concentration above the MIC (termed the mutation prevention concentration) at which selective amplification of single-step, drug-resistant mutants may occur. Such mutants proliferate readily in the absence of competition with the inhibited susceptible cells of the wild-type strain, thereby giving rise to a new resistant population with a higher MIC than that for the wild-type strain. This observation has implications for patients with infections at sites where the penetration of antibiotics is suboptimal, despite the appropriate dosage scheme, e.g. abscesses and endocardial vegetations.
Heteroresistance may be the precursor stage leading to the emergence of a resistant bacterial strain. Recent prevalence in the occurrence of heteroresistant Staphyloccocus aureus resulting in increases in treatment failure and mortality have renewed the urgency for development of methods for the rapid laboratory detection of heteroresistant strains. In order to prevent the spread and/or emergence of heteroresistant strains, antibiotics should be administered with prudence. Shorter antimicrobial regimens that are able to achieve the maximum effectiveness with the minimum selective pressure are necessary. There remains a need in the art for methods of identifying initial dose, maintenance dose and dose frequency necessary to achieve maximum treatment effectiveness with minimal selective pressure.
In light of the above, it is an object of the present invention to provide the desired features described herein as well as additional advantages such as decreasing the potential for on-therapy drug resistance and the spreading and/or emergence of heteroresistant bacterial strains.